Approach 1: To validate the macaque model by reproducing vaccine efficacy similar to that observed in the RV144 HIV vaccine trial. We have demonstrated that the macaque model is able to morror the results in humans.Approach 2: To test the protective potential of CD8+ effector cells and antibodies in the genital and gastrointestinal tracts by using HPV based SIV vaccines and secreted gp96 Ig based SIV vaccines.We have demonstrated that CD8 cells are not sufficient for protection. Rather antibodies to the envelope appear to be necessary. Approach 3: To improve the efficacy of the ALVAC gp120 vaccine regimen by adding CD40L to the vectored vaccine, by changing the adjuvant in the protein boost, MF59 versus Alum, by using the CD4 gp120 FLSC immunogen that exposes cryptic epitopes, and by changing the priming Ad26 versus DNA versus ALVAC. Approach 4: To assess whether non-neutralizing antibodies are the mediators of protection from SIV and study the mechanism. Approach 5: To develop novel polypeptide vaccines for HIV to target seemingly protective epitopes. Approach 6: To assess whether complete protection from HIV/ SIV acquisition can be obtained with vaccination in combination with microbicides.